Aloxi

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with palonosetron, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

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Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Aloxi, there are no specific foods that you must exclude from your diet when receiving this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Aloxi falls into category B. There are no good studies that have been done in humans with Aloxi. But in animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

Tell your doctor if you are breastfeeding or plan to breastfeed. 

It is not known if Aloxi crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Aloxi.

Approximately 50% metabolized, principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2;1 however, pharmacokinetics not substantially different between poor and extensive CYP2D6 substrate metabolizers.1

Does not inhibit activity of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5; effect on isoenzyme 2C19 activity undetermined.1 Does not induce activity of isoenzymes 1A2, 2D6, or 3A4/5.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions are unlikely.1

Drugs Associated with Serotonin Syndrome

Potentially serious, sometimes fatal, serotonin syndrome, particularly with concomitant use of other serotonergic agents.1 (See Serotonin Syndrome under Cautions.)

Monitor patients for serotonin syndrome.1 If serotonin syndrome occurs, immediately discontinue palonosetron and initiate supportive treatment.1

Specific Drugs

Palonosetron has been administered safely with analgesics, anticholinergic agents, antiemetics, antispasmodics, and corticosteroids in clinical studies.1

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

Approximately 62%.1

Elimination

Metabolism

Approximately 50% metabolized (principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2) to 2 metabolites with <1% of the 5-HT3 receptor inhibitor activity of palonosetron.1 However, pharmacokinetics are not substantially different between poor and extensive CYP2D6 substrate metabolizers.1

Elimination Route

Eliminated principally in urine (approximately 80% in 144 hours, about 40% as palonosetron).1

Half-life

Approximately 40 hours.1

Special Populations

Hepatic impairment: Total body clearance not substantially affected.1

Mild to moderate renal impairment: Pharmacokinetics not substantially affected.1

Severe renal impairment: Total systemic exposure increased by approximately 28%.1 Effect of dialysis on pharmacokinetics not studied, but unlikely to have clinically important effect.1

Geriatric patients: In a population pharmacokinetic analysis, no differences in pharmacokinetics observed between cancer patients ≥65 years of age and younger cancer patients (18–64 years of age).1

• Antiemetic activity for acute nausea and vomiting appears to be mediated via inhibition of serotonin activity both centrally (in area postrema and chemoreceptor trigger zone) and peripherally (in GI tract).2 3 4 5 6 8 11 18 19 20

• Alternative mechanisms to peripheral and CNS stimulation by serotonin appear to be responsible for delayed nausea and vomiting.2 3 5 6 7 8 9 10 11 12 13 14 15 16 Risk of delayed nausea and vomiting may be decreased by effective prevention of acute nausea and vomiting in the same chemotherapy cycle.13 20 Palonosetron’s potency and long plasma half-life may contribute to its efficacy in delayed nausea and vomiting.7 11 17 21

• Postoperative nausea and vomiting is influenced by a number of patient-, surgical-, and anesthesia-related factors and is triggered by a release of serotonin in a cascade of neuronal events involving both the CNS and the GI tract.1

• Tell all of your health care providers that you take Aloxi. This includes your doctors, nurses, pharmacists, and dentists.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Hard stools (constipation).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Aloxi is contraindicated in patients known to have hypersensitivity to the drug or any of its components  [see Adverse Reactions (6.2)].

Chemotherapy-Induced Nausea and Vomiting in Adults

Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in three Phase 3 trials and one Phase 2 trial.  In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.

Moderately Emetogenic Chemotherapy
Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V. Aloxi with either single-dose I.V. ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide < 1500 mg/m², doxorubicin > 25 mg/m², epirubicin, irinotecan, and methotrexate > 250 mg/m². Concomitant corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of patients in study 2. The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%).  The mean age was 55 years.

Highly Emetogenic Chemotherapy
A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose I.V. palonosetron from 0.3 to 90 mcg/kg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ≥ 70 mg/m² or cyclophosphamide > 1100 mg/m²).  Concomitant corticosteroids were not administered prophylactically.  Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.

A Phase 3, double-blind trial involving 667 patients compared single-dose I.V. Aloxi with single-dose I.V. ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m², cyclophosphamide  > 1500 mg/m², and dacarbazine.  Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients.  Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy.  The mean age was 52 years.

Efficacy Results
The antiemetic activity of Aloxi was evaluated during the acute phase (0-24 hours) [Table 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.

These studies show that Aloxi was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.  In study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.  Clinical superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute phase.

These studies show that Aloxi was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy.

These studies show that Aloxi was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.

Chemotherapy-Induced Nausea and Vomiting in Pediatrics

One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients. The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of Aloxi 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg). Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m2), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.

Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.

Efficacy Results
As shown in Table 7, intravenous Aloxi 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.

In patients that received Aloxi at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

Postoperative Nausea and Vomiting

In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (Study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery.  All patients received general anesthesia.  Study 1 was a pivotal study conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of post operative nausea and vomiting and/or motion sickness.

In Study 1 patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia. The antiemetic activity of palonosetron was evaluated during the 0 to 72 hour time period after surgery.

Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers.  As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian. The age of patients ranged from 21 to 74 years, with a mean age of 37.9 years.  Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72 hours postoperatively.

Secondary efficacy endpoints included:

• Complete Response (CR) 0-48 and 0-72 hours
• Complete Control (CC) defined as CR and no more than mild nausea
• Severity of nausea (none, mild, moderate, severe)

The primary hypothesis in Study 1 was that at least one of the three palonosetron doses were superior to placebo.

Results for Complete Response in Study 1 for 0.075 mg palonosetron versus placebo are described in the following table.

Palonosetron 0.075 mg reduced the severity of nausea compared to placebo.  Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate I.V. palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy.  Five I.V. palonosetron doses (0.1, 0.3, 1.0, 3.0, and 30 µg/kg) were evaluated in a total of 381 intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery.  The lowest effective dose was palonosetron 1 µg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004.  Palonosetron 1 µg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.